ABSTRACT The public health burden of Treatment Resistant Depression (TRD) has prompted clinical trials of deep brain stimulation (DBS) that have, unfortunately, produced inconsistent outcomes. Potential gaps and opportunities include a need: (1) to better understand the neurocircuitry of the disease; (2) for precision DBS devices that can target brain networks in a clinically and physiologically validated manner; and (3) for greater insight into stimulation dose-response relationships. These needs are based on our overarching hypothesis that network- guided neuromodulation is critical for the efficacy of DBS in TRD. This project aims to address the unmet need of TRD patients by identifying brain networks critical for treating depression and to use next generation precision DBS with steering capability to engage these targeted networks and develop a new therapy for TRD. We use the Boston Scientific (BS) Vercise DBS system, which offers a segmented steerable lead with multiple independent current sources that allows true directional steering. Moreover, this system integrates stimulation field modeling (SFM) with MR tractography to predict network engagement. We use an innovative approach of targeting both subgenual cingulate (SGC) and ventral capsule/ventral striatum (VC/VS), which we term corticomesolimbic DBS. These targets are hubs in distinct yet partially overlapping depression networks and emerging basic science literature implicates them in bidirectional modulation of depression circuits. We also apply a paradigm-shifting approach using intracranial stereo-EEG (sEEG) subacutely after DBS implant to evaluate the clinical reliability of steering, SFMs, and tractography and to define and then target the networks mediating symptoms of depression. In Aim 1, in the Epilepsy Monitoring Unit (EMU), we investigate the capability of Vercise to selectively engage distinct brain networks and compare the spatial distribution of evoked network activity and modulation with that predicted by SFM and tractography. In Aim 2, we conduct further studies in the EMU to delineate depression-relevant networks and show behavioral changes with network-targeted stimulation. We use a variety of tasks to probe different symptom domains and novel assessment tools (Computerized Adaptive Testing and Automated Facial Affect Recognition) to enhance classification and model algorithms to optimize stimulation patterns. In Aim 3, we bring the results from Aims 1 and 2 together, to test the therapeutic potential of corticomesolimbic DBS in 12 subjects with TRD, with a focus on safety, feasibility, and preliminary efficacy in a 8-month open label trial with a subsequent randomized, blinded withdrawal of stimulation to assess efficacy. The impact of this proposal includes physiological validation of current ?steering? DBS technology to target specific networks, insights into effects of stimulation parameters on network physiology, an improved understanding of the pathophysiology of depression, and, perhaps most importantly, a novel approach for treating TRD. This research will also pioneer a novel and high-yield test bed for DBS therapy development consistent with BRAIN priorities.